Int. J. Vitam. Nutr. Res., 77 (3), 2007, 205–216 Effect of Genotype on Micronutrient Absorption and Metabolism: a Review of Iron, Copper, Iodine and Selenium, and Folates Richard Mithen Institute of Food Research, Colney Lane, Norwich, NR4 7UA, UK Received for publication: July 28, 2006 Abstract: For the majority of micronutrients, there are very little data, or none at all, on the role of genetic poly- morphisms on their absorption and metabolism. In many cases, the elucidation of biochemical pathways and regulators of homeostatic mechanisms have come from studies of individuals that have mutations in certain genes. Other polymorphisms in these genes that result in a less severe phenotype may be important in determining the natural range of variation in absorption and metabolism that is commonly observed. To illustrate some of these aspects, I briefly review the increased understanding of iron metabolism that has arisen from our knowledge of the effects of mutations in several genes, the role of genetic variation in mediating the nutritional effects of io- dine and selenium, and finally, the interaction between a genetic polymorphism in folate metabolism and folic acid fortification. Key words: Micronutrients, genetic polymorphisms, iron, iodine, selenium, folates Introduction the interpretation of epidemiological studies, in which some of the variation observed in nutrient status or re- Recently there has been considerable interest in the role quirement may be due to genetic variation at a few or sev- that genetic polymorphisms may play in several aspects eral loci that determine the uptake and metabolism of var- of human nutrition, and the ill-defined terms nutrige- ious nutrients. The increase in interest and knowledge of nomics and nutrigenetics have become commonplace [1]. diet-gene interactions, largely driven by the expansion of For some researchers, this aspect of nutrition is associat- knowledge on the nature of the human genome, is at a time ed with the suggestion that diets can be personalized – that of rapid change in the economic and nutritional status of by knowing one’s genotype it may be possible to fine-tune the population of both developed countries and so-called one’s diet to ensure avoidance of chronic disease. For oth- developing countries. As the health burden of the “west- ers, this science has value in assisting with, for example, ern diet” is rapidly becoming apparent with an increase in DOI 10.1024/0300-9831.77.3.205 Int. J. Vitam. Nutr. Res., 77 (3), 2007, © Hogrefe & Huber Publishers 206 R. Mithen: Genetic Variation and Micronutrients such conditions as obesity and type 2 diabetes, there is a matosis) [2]. Iron deficiency is of particular significance “westernization” of both the economies and diet of many in early childhood and amongst menstruating women, countries in Asia and south and central America. The eco- whereas hemochromatosis is most prevalent in late-mid- nomic expansion of countries such as China, India, and dle-aged men and post-menopausal women. Hereditary Brazil has led to enormous disparities of both income and hemochromatosis leads to the accumulation of iron and nutritional status within these countries. This is also like- eventually to the deposition of iron in vital organs. The ly to be combined with greater genetic susceptibility of specific genetic defects that cause this disorder have been many people within these countries to conditions such as identified and these provide an insight into the manner by type 2 diabetes. Thus, in many countries that were once which iron uptake is regulated. Other polymorphisms in considered “developing” there are issues concerned with these genes may not result in acute hemochromatosis, but both nutrient deficiency and nutrient excess, at least in may still influence iron uptake. terms of the major macronutrients. In humans, iron is strictly conserved. Each day, about The situation regarding micronutrient status (sensu la- 20 mg of iron is recycled from senescent red blood cells to, to include minerals, vitamins, and phytochemicals) is into the synthesis of new red blood cells (Figure 1A). There probably more complex. The issues of sufficient mi- are no pathways in humans for iron excretion, apart from cronutrient intake to prevent deficiency diseases, such as losses in epithelial cells such as skin, gastrointestinal cells, vitamin D and rickets, have now largely (although not en- and urinary tract cells, and fluids such as blood, tears, and tirely) been displaced in many western countries. This has sweat. Thus, absorption of dietary iron must be regulated been replaced by the realization that the nutrient status for to prevent excess iron accumulation [3]. “optimal” health required for the prevention of chronic Heme iron derived from meat is an important source of disease may be quite different for that to prevent defi- iron and is highly bioavailable, although the precise route ciency. Thus, it is considered by many that the level of mi- of uptake is not understood. It is thought that the metal cronutrients within large sections of the western popula- porphyrin ring is split from the globin in the lumen, and tion is below that required for optimal health. Thus, when the intact Fe porphyrin is transported across the brush bor- considering the importance (or otherwise) of genetic vari- der membrane. There are some suggestions that this may ation in determining micronutrient absorption and metab- happen by endocytosis, and a brush border heme recep- olism, we need to consider both that required to prevent tor, HCP1, has been reported [4]. Within the enterocyte, deficiency diseases, and that required for “optimal” health, ferrous ions may be released from the heme and enter a or the reduction in risk of chronic disease. common pool with non-heme iron [5]. Thus subsequent- For the majority of micronutrients, there are very little ly, the basolateral transfer of iron, and its regulation, may data, or none at all, on the role of genetic polymorphisms be the same as for both heme and non-heme iron (Figure on their absorption and metabolism. In many cases, the 1B). elucidation of biochemical pathways and regulators of The pathway of absorption of non-heme iron is better homeostatic mechanisms have come from studies of indi- understood. Within the lumen, iron is likely to be ferric viduals that have mutations in certain genes. Other poly- ion and is poorly available. Fe3+ ions may be chelated (e.g. morphisms in these genes that result in a less severe phe- with phytate or citrate) or encased as a multi-ion form such notype may be important in determining the natural range as ferritin. Fe3+-phytate is poorly absorbed, but ferritin may of variation in absorption and metabolism that is com- be absorbed, although the precise route is yet to be dis- monly observed. To illustrate some of these aspects, I covered. Ferric reductase activity within the duodenal mu- briefly review the increased understanding of iron metab- cosa converts Fe3+ to Fe2+ ion. The cytochrome B DcytB olism that has arisen from our knowledge of the effects of is the most likely candidate for the ferric reductase, but mutations in several genes, the role of genetic variation in the lack of phenotype with DcytB knockout mice suggests mediating the nutritional effects of iodine and selenium, that there may be other ferric reductases [5]. Ferrous ions and finally, the interaction between a genetic polymor- are transported into enterocytes via the divalent metal phism in folate metabolism and folic acid fortification. transporter (DMT1, also known as DCT1 or Nramp2). It seems likely that DMT1 can also transport other divalent ions such as Zn2+, Co2+, Mn2+, and Cd2+, although the phys- iological significance of this is not clear, and these ions Polymorphism in genes affecting may have other transport routes into enterocytes. Once inorganic iron uptake and transport within the enterocyte Fe2+ may either be bound to ferritin or exported into the bloodstream (Figure 1B). The trans- The interaction between diet and genetic factors can lead port of Fe2+ into the circulatory system is due to the coor- to both iron deficiencies and iron overload (hemochro- dinated expression and action of the transport protein fer- Int. J. Vitam. Nutr. Res., 77 (3), 2007, © Hogrefe & Huber Publishers R. Mithen: Genetic Variation and Micronutrients 207 A Senescent red blood cells Spleen Liver Fe, IL-6, O 2 Ceruloplasmin ~ 20 mg Fe /day e- Hepcidin 2+ 3+ 3+ Fe Fe Plasma Fe 2-Tf 20 mg Fe /day Intestinal uptake 1-2 mg Fe /day (Figure 2) Bone marrow (Figure 3) Heme Heme receptor (HCP1) ? B Fe Fe Fe 2+ ? Fe DcytB HO Ferroportin 1 Fe 3+ 2+ 3+ 3+ Ferritin Fe Fe Fe 2-Tf Fe 2+ e- DMT1 Hephaestin Heme Heme receptor (HCP1) ? C Fe liver Fe Fe 2+ ? Fe DcytB HO Ferroportin 1 Fe 3+ Hepcidin Figure 1: A. Model for the Ferritin Fe 2+ recycling of iron and homeostat- Fe 2+ DMT1 Hephaestin ic control mediate by hepcidin. B. Enterocyte model for the uptake of heme and non-heme iron from the lumen. C. Regula- tion of uptake via hepcidin. Int. J. Vitam. Nutr. Res., 77 (3), 2007, © Hogrefe & Huber Publishers 208 R. Mithen: Genetic Variation and Micronutrients roportin 1 (also known as IREG1) and hephaestin on the Mutations in other genes that probably affect hepcidin basolateral surface of the enterocyte [6]. Hephaestin (a Cu- expression can also result in similar phenotypes. For ex- containing protein – see below), which has a high degree ample, those in TFR2 are much rarer than the mutations of homology with the serum ferroxidase ceruloplasmin, in HFE, but can result in a similar phenotype. Likewise, results in the oxidation of ferrous to ferric ion, which then the infrequent mutations in HJV, causing acute juvenile binds to transferrin (Tf) and is transported in the serum.